Shooting for Selective Druglike G-Quadruplex Binders: Evidence for Telomeric DNA Damage and Tumor Cell Death

2012 ◽  
Vol 55 (22) ◽  
pp. 9785-9792 ◽  
Author(s):  
Sandro Cosconati ◽  
Angela Rizzo ◽  
Roberta Trotta ◽  
Bruno Pagano ◽  
Sara Iachettini ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Cell ◽  
Telomeric Dna ◽  
Tumor Cell Death ◽  
G Quadruplex

Photodynamic Therapy with Liposomal Zinc Phthalocyanine and Tirapazamine Increases Tumor Cell Death via DNA Damage

2017 ◽  
Vol 13 (2) ◽  
pp. 204-220 ◽  
Author(s):  
Mans Broekgaarden ◽  
Ruud Weijer ◽  
AlbertC. van Wijk ◽  
RuudC. Cox ◽  
MaartenR. Egmond ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Tumor Cell ◽  
Zinc Phthalocyanine ◽  
Tumor Cell Death

scholarly journals VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Navarro-Carrasco ◽  
Pedro A. Lazo
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Cell ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Tumor Cell Death ◽  
Damage Response ◽  
Parp 1

BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.

scholarly journals Cellular cytotoxicity is a form of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000325 ◽  
Author(s):  
Luna Minute ◽  
Alvaro Teijeira ◽  
Alfonso R Sanchez-Paulete ◽  
Maria C Ochoa ◽  
Maite Alvarez ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Immunogenic Cell Death ◽  
Cell Debris ◽  
Tumor Cell Death ◽  
Mhc Multimer

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.

New marker of tumor cell death revealed by ATR-FTIR spectroscopy

2011 ◽  
Vol 399 (8) ◽  
pp. 2771-2778 ◽  
Author(s):  
Lucia Di Giambattista ◽  
Deleana Pozzi ◽  
Paola Grimaldi ◽  
Silvia Gaudenzi ◽  
Stefania Morrone ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Ftir Spectroscopy ◽  
Tumor Cell Death

Apoptotic tumor-cell death in response to cell proliferation is influenced by p53 status in resected non-small cell lung cancer

Lung Cancer ◽  
2002 ◽  
Vol 36 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Fumihiro Tanaka ◽  
Tetsuya Takata ◽  
Tomoko Yamada ◽  
Kazuhiro Yanagihara ◽  
Yosuke Otake ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Death ◽  
Tumor Cell ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tumor Cell Death ◽  
Apoptotic Tumor Cell ◽  
P53 Status

Apoptosis and Tumor Cell Death in Response to HAMLET (Human α-Lactalbumin Made Lethal to Tumor Cells)

2007 ◽  
pp. 217-240 ◽  
Author(s):  
Oskar Hallgren ◽  
Sonja Aits ◽  
Patrick Brest ◽  
Lotta Gustafsson ◽  
Ann-Kristin Mossberg ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Cell Death
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